Ephrin receptors (EPH), the largest family of receptor tyrosine kinases, are type-I transmembrane proteins that bind with ephrin ligands (EFN). Receptors in the EPH subfamily typically have a single kinase domain and an extracellular region containing a Cys-rich domain and 2 fibronectin type III repeats. Based upon sequence analyses, ephrin ligands can be divided into two groups: ephrin-A ligands (EFNA) and three ephrin-B ligands (EFNB). EFNA ligands (i.e., EFNA1, EFNA2, EFNA3, EFNA4, EFNA5, EFNA6) are typically anchored to the cell surface via glycosyl phosphatidylinositol (GPI) linkages, although some non-GPI-anchored proteins are produced through alternative splicing of ephrin mRNAs, such as EFNA4. EFNB ligands (i.e. EFNB1, EFNB2, EFNB3) contain a transmembrane domain and a short cytoplasmic region with conserved tyrosine residues and a PDZ-binding motif. EFNA ligands preferentially bind with any of the nine different ephrin A receptors (EPHA) (i.e., EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHA9), whereas EFNB ligands preferentially bind with any of six different ephrin B receptors (EPHB) (i.e. EPHB 1, EPHB2, EPHB 3, EPHB4, EPHB 5, EPHB 6), although some cross-interactions have been reported.
EFN-EPH signaling can be bi-directional (impacting both the ligand- and receptor-expressing cells) and regulates a broad range of biological activities including neural development, cell patterning, angiogenesis, and cell motility and invasion. In the context of cancer, the expression of various EPHs and EFNs has been observed, and various functions have been reported (Hafner et al., Clinical Chemistry 50(3):490-499, 2004; Surawska et al., Cytokine & Growth Factor Reviews 15(6):419-433, 2004; Pasquale, E. B, Nature Reviews Cancer 10(3):165-180, 2010). Due to ligand-receptor binding promiscuity as well as functional overlap, it has been difficult to precisely define the roles of each EFN and EPH. While therapeutic targeting of the EPH receptors for the treatment of cancer has been explored targeting of EFN ligands has not been pursued to any great extent (Pasquale, E. B., Nature Reviews Cancer 10(3):165-180, 2010).
There remains a significant need for additional therapeutic options for cancers. To this end, the present invention provides novel antibody-drug conjugates that target EFNA4-positive cancers.